Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5355—Non-condensed oxazines and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
  • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

• the present invention relates to a medicine, particularly a novel furanone derivative having an inhibitory effect on Cdc7 or a pharmaceutically acceptable salt thereof.
• Cancer is a group of diseases caused by uncontrolled, unlimited growth of cells within a living body. Since cancer cells usually grow faster than normal cells, cancers would be capable of being treated by controlling the replication of DNA during the cell division, particularly during the division of chromosomes. Actually, gemcitabine, which has the effect of inhibiting DNA replication, is widely used in the treatment of non-small cell lung cancer, pancreatic cancer, biliary tract cancer, bladder cancer, breast cancer, ovarian cancer, or others.
• Cdc7 is a serine-threonine protein kinase and is an enzyme which is essential for the initiation of DNA replication in the cell cycle. Specifically, Cdc7 forms a complex with cofactors such as Dbf4 (ASK), and phosphorylates its substrate, MCM (mini-chromosome maintenance) proteins. It is supposed that this phosphorylation results in assembly of Cdc45 and a DNA polymerase on the DNA to form an MCM complex, thereby initiating the DNA replication (see Non Patent Literature 1). Furthermore, it has been shown in a recent study that Cdc7 plays an important role not only in the replication of DNA, but also in DNA damaging pathways (see Non Patent Literature 2).
• Cdc7 has drawn attention as a target of anti-cancer agents, and active researches on Cdc7 have been made.
• CDC7 is overexpressed not only in common established cell lines derived from human tumors, but also in cells taken from live tissues, such as breast cancer, colon cancer, and lung cancer (see Non Patent Literature 3).
• Non Patent Literature 4 it was shown, in more recent days, that CDC7 is overexpressed in p53-mutated triple negative (ER-/PR-/Her2-) breast cancer cells (see Non Patent Literature 4), and thus it has been expected that Cdc7 will be a promising target molecule against a triple negative type of breast cancer, which has been considered to be difficult to treat.
• An object of the present invention is to provide a medicine, particularly a novel furanone derivative having an inhibitory effect on Cdc7 or a pharmaceutically acceptable salt thereof.
• the present invention is achieved by the following (1) to (3):
• the present inventors have made various studies in order to solve the above-mentioned problem, and found that novel furanone derivatives represented by the formula (I) and pharmaceutically acceptable salts thereof had excellent inhibitory effect on Cdc7, resulting in completion of the present invention.
• the compounds provided by the present invention are capable of controlling the growth of cells. Therefore, the compounds of the present invention having an inhibitory effect on Cdc7 will be useful as a medicine, particularly an agent for the treatment of diseases derived from abnormal growth of cells, such as cancers.
• a novel furanone derivative of the present invention is a compound represented by the formula (I): wherein A represents -COOR1 or a hydrogen atom; R1 represents a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocycle; R2 and R3 are the same or different and each independently represent a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted phenyl group, an optionally substituted heterocycle, an optionally substituted heterocyclic fused ring, or an optionally substituted amino group; or alternatively, R2 and R3, taken together with the nitrogen atom to which they are attached, may form an optionally substituted heterocycle or an optionally substituted heterocyclic fused ring; and R4 represents a hydrogen atom or a halogen atom; with the proviso that when A represents -COOR1, R2 and R3 are not optionally substituted amino groups at the same time, and when A represents a hydrogen atom, R3 represents a hydrogen atom.
• A represents
• the heterocyclic moiety of an optionally substituted heterocycle is selected from an alicyclic heterocyclic group and an aromatic heterocyclic group.
• An alicyclic heterocyclic group is a 3- to 8-membered heterocyclic group containing at least one heteroatom selected from a nitrogen atom, a sulfur atom, and an oxygen atom.
• Specific examples of the alicyclic heterocyclic group include pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, etc.
• An aromatic heterocyclic group is a 5- or 6-membered monocyclic aromatic heterocyclic group containing at least one heteroatom selected from a nitrogen atom, a sulfur atom, and an oxygen atom.
• Specific examples of the aromatic heterocyclic group include imidazolyl, pyrazolyl, thienyl, thiazolyl, pyridyl, etc.
• the heterocyclic fused ring moiety of an optionally substituted heterocyclic fused ring is, for example, a fused heterocyclic group which is bicyclic by fusing 3- to 8-membered rings and which contains at least one heteroatom selected from a nitrogen atom, a sulfur atom, and an oxygen atom.
• a fused heterocyclic group which is bicyclic by fusing 3- to 8-membered rings and which contains at least one heteroatom selected from a nitrogen atom, a sulfur atom, and an oxygen atom.
• the fused heterocyclic group include benzothiophenyl, benzimidazolyl, indazolyl, benzoxazolyl, benzothiazolyl, indolyl, isoquinolyl, phthalimide, etc.
• an optionally substituted amino group is an amino group having a linear, branched, or cyclic alkyl, aryl, or heteroaryl group which is substituted or unsubstituted and containing 1 to 6 carbons, for example, an amino group to which an alkyl group, an alkylamino group, an aryl group, a heteroaryl group, a heterocyclic group, a heterocyclic fused ring group, or the like which is unsubstituted or substituted with one or more substituents may be attached.
• the "one or more substituents" in these groups attached to an amino group are selected from a halogen atom, a substituted or unsubstituted alkyl group, alkenyl group, alkynyl group, alkoxy group, an amino group, a nitro group, a cyano group, a hydroxy group, alkylamino group, a carbamoyl group, a carboxyl group, a formyl group, an acetyl group, and a benzoyl group.
• substituted hydrocarbon group an optionally substituted heterocycle, an optionally substituted phenyl group, or an optionally substituted heterocyclic fused ring is/are be one or more substituents selected from a halogen atom, alkyl group, alkoxy group, a amino group, a nitro group, a cyano group, a hydroxy group, alkylamino group, a carbamoyl group, a carboxyl group, a formyl group, an acetyl group, and a benzoyl group.
• the heterocyclic group in the case where R2 and R3, taken together with the nitrogen atom to which they are attached, form an optionally substituted heterocycle or an optionally substituted heterocyclic fused ring is, for example, a 3- to 8-membered heterocyclic group containing at least one heteroatom selected from a nitrogen atom, a sulfur atom, and an oxygen atom, or a fused alicyclic heterocyclic group which is bicyclic by fusing 3- to 8-membered rings and which contains at least one heteroatom selected from a nitrogen atom, a sulfur atom, and an oxygen atom.
• heterocyclic groups include pyrrolidinyl, piperidyl, morpholinyl, thiomorpholinyl, azepinyl, diazepinyl, dihydroisoquinolyl, tetrahydroisoquinolyl, tetrahydroquinolyl, isoindolinyl, indolinyl, tetrahydrobenzazepinyl, benzazepinyl, benzodiazepinyl, benzoxyazepinyl, benzothiazepinyl, etc.
• a halogen atom includes, for example, fluorine, chlorine, bromine, and the like.
• a compound (I) of the present invention may have isomers, for example, depending on the type of its substituents. In the specification, such a compound is sometimes described by the chemical structure of only one of its isomeric forms. However, the present invention includes all of the structurally possible isomers of such a compound (geometrical isomers, optical isomers, tautomers, etc.), and also include its individual isomers or mixtures thereof.
• a pharmaceutically acceptable salt of a compound (I) of the present invention includes a salt with an inorganic acid, such as hydrochloric acid, sulfuric acid, carbonic acid, and phosphoric acid, and a salt with an organic acid, such as formic acid, acetic acid, fumaric acid, maleic acid, methanesulfonic acid, and p-toluenesulfonic acid.
• an inorganic acid such as hydrochloric acid, sulfuric acid, carbonic acid, and phosphoric acid
• an organic acid such as formic acid, acetic acid, fumaric acid, maleic acid, methanesulfonic acid, and p-toluenesulfonic acid.
• a salt with an alkali metal such as sodium and potassium
• a salt with an alkaline earth metal such as magnesium and calcium
• a salt with an organic amine such as a lower alkyl amine and a lower alcohol amine
• a salt with a basic amino acid such as lysine, arginine, and ornithine, and in addition, an ammonium salt.
• Compounds (I) of the present invention and pharmaceutically acceptable salts thereof can be produced, for example, by the methods mentioned below.
• the production methods mentioned below when a defined group is changed under conditions where the method is performed, or when a defined group is not suitable for performing the method, the production can be easily achieved by applying methods usually used in organic synthetic chemistry, such as procedures for protection and deprotection of functional groups [ T. W. Greene, Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, Inc., 1999 ].
• the order of reaction steps for example, those for introducing a substituent or substituents, may be changed as needed.
• a compound (Ia) wherein A is -COOR1 can be produced, for example, by scheme 1: wherein R1, R2, R3 and R4 have the same meaning as mentioned above.
• a compound (Ia) of the present invention can be obtained by heating and reacting a compound (III) and 1 to 5, preferably 1 to 1.5, molar equivalents of a compound (IV) in a solvent under conditions for a Knoevenagel condensation reaction, that is, in the presence of a catalytic base such as piperidine.
• the solvent can be any solvent which is inert in the reaction, and is not limited in particular.
• a lower alcohol, preferably ethanol can be used as the solvent.
• piperidine or proline for example, can be used in an amount of from a catalytic amount to an equivalent amount relative to the compound (III).
• the reaction can be carried out in the range of from room temperature to reflux temperature and for a period of 3 hours to 2 weeks.
• the reaction can be carried out for 1 to 3 days under conditions of reflux in ethanol, thereby to synthesize the compound.
• this reaction can also be performed under other usual conditions used in the Knoevenagel condensation reaction, for example, under acidic conditions using hydrochloric acid, acetic acid, or the like, to produce the compound.
• the compound (IV) which can be used as one starting material in scheme 1 is commercially available (for example, from SIGMA-ALDRICH) or can be obtained by known methods (see, for example, Rajesh H. Bahekar et al., Bioorganic & Medicinal Chemistry, 15 (21), 6782-6795 (2007 ); and Seung-Jun Oh et al., Bioorganic & Medicinal Chemistry, 12 (21), 5505-5513 (2004 )).
• the compound (III) which can be used as the other starting material in scheme 1 can be produced, for example, by the procedures shown in scheme 2 or 3. wherein R1, R2, and R3 have the same meaning as mentioned above, and R1' represents a substituted or unsubstituted lower alkyl group.
• a compound (VII) can be obtained by converting a malonic diester (V) to its enolate with a base, such as sodium hydride, in a solvent, such as anhydrous tetrahydrofuran, followed by reaction with chloroacetyl chloride (VI).
• a base such as sodium hydride
• a solvent such as anhydrous tetrahydrofuran
• the compound (III) can be obtained by reacting the compound (VII) obtained in the previous step and an amine (VIII) in an amount of from an equivalent amount to an excess amount, preferably in an amount of 1.2 to 3 molar equivalents, in a solvent at room temperature or at heated temperature.
• the solvent can be any solvent which is inert in the reaction, and is not limited in particular.
• tetrahydrofuran, dimethylformamide, ethanol, and the like can be used as the solvent.
• the reaction is dependent on the reactivity of the amine (VIII) used, and generally is completed in a period of 1 hour to 1 day at a temperature of from room temperature to the reflux temperature of the solvent.
• a base such as sodium hydride, sodium hydroxide, triethylamine, or the like, in an amount of from an equivalent amount to an excess amount.
• the compound (III) can also be produced by mean of a sequence of reactions without isolating the compound (VII), by known methods (see, for example, Sheng-Chu Kuo et al., Chem. Pharm. Bull., 36 (11), 4403-4407 (1988 )) or their modified methods. That is, the compound (III) can be obtained by adding the amine (VIII) in an amount of from an equivalent amount to an excess amount, preferably in an amount of 1.2 to 3 molar equivalents, to the solution after the reaction in step 2-1, and performing the reaction at room temperature or at heated temperature.
• the malonic diester (V) and the amine (VIII) which can be used as the starting materials in scheme 2 are commercially available or can be obtained by known methods. wherein R1 and R2 have the same meaning as mentioned above.
• a compound (IIIa) wherein R3 is a hydrogen atom can be produced by known methods (see, for example, Robert A. Mack et al., J. Med. Chem., 31 (10), 1910-1918 (1988 )) or their modified methods. That is, the compound (IIIa) can be obtained by cyclocondensation of a compound (IX) with 1 to 5, preferably 1 to 1.5, molar equivalents of isocyanate (X) in a solvent in the presence of a base, such as triethylamine.
• the solvent can be any solvent which is inert in the reaction, and is not limited in particular.
• diethyl ether or ethyl acetate, or mixed solvents thereof can be used as the solvent.
• the reaction can be carried out in the range of from ice-cooled temperature to reflux temperature and for a period of 30 minutes to 1 day. Preferably, the reaction can be carried out at room temperature for 1 to 3 hours, thereby to synthesize the compound.
• a compound (Ia) of the present invention can also be produced by a transesterification reaction of a compound (Ia'), which is a lower alkyl ester compound, as shown in scheme 4: wherein R1, R2, R3, and R4 have the same meaning as mentioned above, and R1' represents a substituted or unsubstituted lower alkyl group.
• a compound (Ia) of the present invention can be produced by a transesterification reaction of the compound (Ia') by known methods (see, for example, Takanori Iwasaki et al., J. Org. Chem., 73 (13), 5147-5150 (2008 )) or their modified methods. That is, the compound (Ia) can be obtained by heating and reacting the compound (Ia') and an excess amount, preferably more than 10 molar equivalents, of an alcohol (XI) in a solvent in the presence of a tetranuclear zinc cluster catalyst.
• the solvent can be any solvent which is inert in the reaction, and is not limited in particular.
• dimethylacetamide, 1,4-dioxane, diisopropyl ether, or the like can be used as the solvent.
• the alcohol (XI) may be used as the solvent.
• the tetranuclear zinc cluster catalyst catalysts which are commercially available (for example, under a product name of ZnTAC24, from STREM CHEMICALS) or are produced by the method described in the above-mentioned reference are used and added in a catalytic amount, preferably in an amount of 1 to 10% molar equivalents.
• a tertiary amine such as dimethylaminopyridine or triethylamine, is added in an amount of from a catalytic amount to 1 molar equivalent to accelerate the reaction.
• the reaction can be carried out in the range of from room temperature to reflux temperature and for a period of 1 hour to 1 week. Preferably, the reaction can be carried out for 1 to 3 days under reflux conditions, thereby to synthesize the compound. Alternatively, the reaction may also be carried out using a microwave reactor, for example, for a period of from several minutes to several hours under temperature conditions of 60 to 150°C, thereby to synthesize the compound.
• This reaction can also be carried out under other usual conditions used in the transesterification reaction, as shown in scheme 5, for example, under acidic or basic conditions, or under conditions using a catalyst, such as tetravalent titanium.
• a catalyst such as tetravalent titanium.
• a compound (Ib) of the present invention can be obtained by hydrolysis of a compound (Ia'), which is a lower alkyl ester compound, under reaction conditions used in usual organic synthetic chemistry (using methods described in, for example, T. W. Greene, Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, Inc., 1999, p. 377 , or their modified methods). That is, the compound (Ib) can be obtained by reacting the compound (Ia') and a base or acid in an amount of from an equivalent amount to an excess amount in a solvent at a temperature between 0°C and the boiling point of the solvent used.
• the solvent can be any solvent which is inert in the reaction, and is not limited in particular.
• 1,4-dioxane, tetrahydrofuran, various alcohols, or the like can be used as the solvent.
• base or acid use can be made of, for example, sodium hydroxide, potassium hydroxide, or hydrochloric acid.
• the reaction can be carried out at a temperature between 0°C and the boiling point of the solvent used and for a period of 1 hour to 1 week. Preferably, the reaction can be carried out for 1 hour to 1 day under reflux conditions, thereby to synthesize the compound.
• a compound (Ic) wherein A and R3 are hydrogen atoms can be produced, for example, as shown in scheme 6: wherein R2 and R4 have the same meaning as mentioned above, and R1" represents a hydrogen atom or a substituted or unsubstituted lower alkyl group.
• a compound (Ic) of the present invention can be synthesized from a compound (Ia"), which is a compound (Ia) wherein R1 is a substituted or unsubstituted lower alkyl ester group and R3 is hydrogen, using known methods (see, for example, Sheng-Chu Kuo et al., Chem. Pharm. Bull., 38 (2), 340-341 (1990 )) or their modified methods.
• the reaction can be carried out by heating a solution or suspension of a compound (Ia") in N,N-dimethylformamide or N,N-dimethylacetamide at a temperature between 100°C and the boiling point of the solvent used and for a period of 1 to 24 hours.
• the reaction can be carried out for 1 to 12 hours under reflux conditions, thereby to synthesize the compound.
• This reaction can also be carried out by heating and stirring in the presence of a base.
• the reaction can be carried out by heating to reflux in an alcohol solvent, such as ethanol, in the presence of a highly-concentrated aqueous solution of potassium hydroxide, thereby to synthesize compound.
• a compound (I) of the present invention which has a desired functional group at a desired position can be obtained by combining the above-mentioned methods as appropriate and carrying out procedures usually used in organic synthetic chemistry (for example, reactions for alkylation of amino groups, reactions for oxidation of an alkylthio group to the corresponding sulfoxide or sulfone group, reactions for converting an alkoxy group to a hydroxy group or vice versa).
• Compounds (I) of the present invention or pharmaceutically acceptable salts thereof can be used as medicines, particularly anti-tumor agents, in the form of conventional pharmaceutical preparations for oral administration or for parenteral administration, such as instillation.
• compositions for oral administration include solid formulations, such as tablets, granules, powders, and capsules, and liquid formulations, such as syrups. These formulations can be prepared by conventional methods. Solid formulations can be prepared using conventional pharmaceutical carriers like lactose, starches such as corn starch, crystalline cellulose such as microcrystalline cellulose, hydroxypropylcellulose, calcium carboxymethylcellulose, talc, magnesium stearate, and others. Capsules can be prepared by encapsulating the granules or powders thus prepared. Syrups can be prepared by dissolving or suspending a compound (I) of the present invention or a pharmaceutically acceptable salt thereof in an aqueous solution containing sucrose, carboxymethylcellulose, or the like.
• compositions for parenteral administration include formulations for injection, such as instillation.
• Formulations for injection can also be prepared by conventional methods, and may be incorporated in tonicity adjusting agents (for example, mannitol, sodium chloride, glucose, sorbitol, glycerol, xylitol, fructose, maltose, mannose), stabilizing agents (for example, sodium sulfite, albumin), antiseptics (for example, benzyl alcohol, methyl p-hydroxybenzoate) as appropriate.
• tonicity adjusting agents for example, mannitol, sodium chloride, glucose, sorbitol, glycerol, xylitol, fructose, maltose, mannose
• stabilizing agents for example, sodium sulfite, albumin
• antiseptics for example, benzyl alcohol, methyl p-hydroxybenzoate
• Tumors include solid tumors, such as breast cancer, colon cancer, and lung cancer, and hematological cancers, such as leukemia, lymphoma, and myeloma.
• the amount of dosage of a compound (I) of the present invention or a pharmaceutically acceptable salt thereof can be varied, according to the severeness of the disease, the age and body weight of the patient, its dosage form, and others, and usually is in the range of 1 mg to 1,000 mg per day for adult humans, which can be administered once, or twice or thrice by oral route or by parenteral route.
• Diethyl malonate (5.0 mL, 0.033 mol) was added dropwise to a solution of sodium hydride (60% w/w in oil, 2.7 g, 0.066 mol) in anhydrous tetrahydrofuran (50 mL) that cooled with ice bath. The mixture was refluxed for 5 min. The reaction mixture was cooled with ice bath, chloroacetyl chloride (2.8 mL, 0.035 mol) was added dropwise to the reaction mixture and the mixture was stirred for 1 h then stirred at 45 °C for 1 h.
• Example 86 A solution of the compound (0.040g, 0.10mmol) of Example 86 and zinc cluster catalyst (Zn 4 (OCOCF 3 ) 6 O) (0.0012 g, 0.0013 mmol) in 2-propanol (0.5 mL) was stirred at 95 °C for 4 days. Cooled to ambient temperature, the reaction mixture was purified by preparative HPLC to afford the titled compound as solid (0.0061 g, y. 13%).
• N,N-Dimethyl-1-(3-methyl-4-nitrophenyl)methanamine (0.80 g, 4.1 mmol) was dissolved in ethanol (5.0 mL) and 10% palladium on carbon (0.18 g) was added at ambient temperature. The reaction mixture was agitated under a hydrogen atmosphere at ambient temperature for 4 h. Palladium on carbon was removed by filtration with Celite and the solvent was removed under reduced pressure to afford 4-[(dimethylamino)methyl]-2-methylaniline (0.65 g, y. 96%).
• reaction mixture was cooled to ambient temperature then hexamethyleneimine (0.071 mL, 0.63 mmol) was added dropwise and the mixture was stirred at ambient temperature for further 1 h.
• the reaction mixture was diluted with water, and extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel, eluted with chloroform/methanol to afford 2-methoxyethyl 2-azepinyl-4-oxo-4,5-dihydrofuran-3-carboxylate as oil (0.065 g, y. 43%).
• the titled compound was similarly prepared as solid according to the procedure described in the Example 1, using ethyl 2- ⁇ [2-methyl-4-(2-pyridinylmethoxy)phenyl]amino ⁇ -4-oxo-4,5-dihydrofuran-3-carboxylate which similarly prepared according to the procedure described in the Example 74, First step to Fourth step and 7-azaindole-3-carboxaldehyde as starting materials.

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